Changes in LTP/LTD at 26

Cognitive Impairment at 17

Cognitive impairment manifests at 4 months as a deficit in long-term retention and correlates with the accumulation of intraneuronal Aβ in the hippocampus and amygdala, but plaques and tangles are not yet apparent (Billings et al., 2005).

Age-related, progressive neuropathology including plaques and tangles. Extracellular Aβ deposits by 6 months in frontal cortex, more extensive by 12 months. No tau pathology at 6 months, but evident at 12 months. Synaptic dysfunction, including LTP deficits, prior to plaques and tangles.

Cognitive impairment by 4 months. Impairments first manifest as a retention/retrieval deficit and not as a learning deficit, and occur prior to plaques and tangles. Deficits in both spatial and contextual based paradigms. Clearance of intraneuronal Aβ by immunotherapy rescues the early cognitive deficits in a hippocampal-dependent task.

Observed

Plaques at 7

Amyloid deposition begins at 1.5 months and reaches high levels especially in subiculum and deep cortical layers. Aβ42 also accumulates intraneuronally in an aggregated form within the soma and neurites starting at 1.5 months (Oakley et al., 2006).

Neuronal Loss at 39

Neuron loss in cortical layer 5 and subiculum.

Gliosis at 9

Gliosis begins at 2 months (Oakley et al., 2006).

Synaptic Loss at 39

Synaptic markers synaptophysin, syntaxin, and PSD-95 decrease with age and are significantly reduced by 9 and 12 months.

Changes in LTP/LTD at 26

LTP is normal in young animals, but becomes impaired around 6 months (Kimura et al., 2009); specifically, in hippocampal slices from < 4-month-old mice, I/O curves of fEPSPs were not different from those of wild-type controls, but the I/O responses at Schaffer collateral-CA1 synapses at 6 months were impaired.

Observed

Plaques at 26

Congophillic, dense-core amyloid plaques first appear at 6 months, and increase in size and number with age. Amyloid plaques can occupy more than 25% of the neocortex and hippocampus in 24 month-old mice (Sturchler-Pierrat et al., 1997; Calhoun et al., 1998).

Neuronal Loss at 61

Neuronal loss (14-28%) has been reported in the CA1 region of the hippocampus in 14-18 month old mice (Calhoun et al., 1998).

Unknown

Aβ deposits first observed at 6 months. Congophilic plaques increase in size and number with age and are surrounded by activated microglia, astrocytes, and dystrophic neurites containing hyperphosphorylated tau (although no neurofibrillary tangles). Neuronal loss in the CA1 region of the hippocampus. Mice also develop CAA, and microhemorrages occur at later ages.

Spatial memory defects in Morris Water maze at 3 months and progresses with age. Memory deficits in passive avoidance were observed in 25 month-old mice, but not at younger ages.

Observed

Neuronal Loss at 104

Neuronal loss, as measured by NeuN staining, was observed in the CA3 region of the hippocampus at 24 months of age. Neuronal loss was not detected in the cerebral cortex at this time.

Gliosis at 52

At 12 months of age, microgliosis is seen in transgenic mice, as measured by the presence of Iba-1 staining in the hippocampus and cortex. Astrocytosis, as measured by GFAP-reactivity, increased starting around 18 months of age in these regions.

Synaptic Loss at 34

Starting around eight months of age, transgenic mice exhibit a decrease in synaptic density in the CA3 region of the hippocampus as measured by synaptophysin staining.

Changes in LTP/LTD at 35

By eight months of age, transgenic mice exhibit reduced short term plasticity as measured by paired-pulse facilitation in addition to reduced LTP as elicited by high frequency stimulation to the perforant pathway.

Unknown

Age-dependent accumulation of Aβ oligomers within hippocampal and cortical neurons, but negligible deposits of extracellular amyloid. Abnormal tau phosphorylation, but no overt tangle pathology. Synaptic loss and gliosis in hippocampus and cerebral cortex. Late neuronal loss in the CA3 region of the hippocampus.

Memory impairment by eight months as measured by the Morris water maze. Specifically, reduced spatial reference memory in the Morris water maze compared to mice expressing comparable levels of wild-type human APP.

Synaptic Loss at 39

Cognitive Impairment at 78

Memory impairment in homozygous mice at 18 months as measured by the Y maze test. APPNL/NL mice (with Swedish mutation only) were unimpaired at this age. No significant deficit was seen in the Morris water maze at 18 months.

Absent

Tangles at

Absent; although elevated levels of phosphorylated tau are observed in dystrophic neurites around plaques.

Observed

Plaques at 6

Aβ deposition begins at 6 weeks of age in the cortex and 3-4 months of age in the hippocampus (Radde et al., 2006).

Neuronal Loss at 74

Global neuron loss is not observed, but modest neuron loss was found in the granule cell layer of the dentate gyrus and other subregions with high neuronal density in 17-month old animals (Rupp et al., 2011).

Gliosis at 6

Activated microglia around Aβ deposits at 6 weeks as well as increased astrogliosis (Radde et al., 2006). Levels of CCL2 and TNFα increase at later ages (Lee et al., 2010).

Synaptic Loss at 10

Dendritic spine loss around plaques reported to begin approximately 4 weeks after plaque formation and continue for several months (Bittner et al., 2012).

Changes in LTP/LTD at 35

Hippocampal CA1 LTP normal at 4.5 months of age, but impaired at 8 and 15 months of age (Gengler et al., 2010).

Unknown

Amyloid plaque deposition starts at approximately 6 weeks in the neocortex. Amyloid deposits in the hippocampus appear at 3-4 months, and in the striatum, thalamus and brainstem at 4-5 months. Phosphorylated tau-positive neuritic processes have been observed in the vicinity of all congophilic amyloid deposits, but no fibrillar tau inclusions are seen.

Cognitive deficits in spatial learning and memory in the Morris water maze reported at 7 months. Impaired reversal learning of a food-rewarded four-arm spatial maze task at 8 months.

Plaques especially in the thalamus and subiculum. Aggregated, hyperphosphorylated tau tangles. Neuronal loss especially of NPY neurons in the hippocampus and subiculum. More severe pathology than Tg-SwDI alone.

Severe learning and memory deficits. Impaired spatial memory compared to Tg-SwDI as measured by the radial arm maze and the Barnes maze at 52-56 weeks.

Synaptic Loss at

Cognitive Impairment at

By 14-16 months, homozygotes have diffuse and compact Aβ deposits in the frontal cortex, by 18-20 months plaques throughout the cortex and olfactory bulb with occasional deposits in the corpus callosum and hippocampus. No tangles, but some changes in phosphorylated tau. Reactive astrocytes and microglia by 14-16 months.

Observed

Plaques at 26

Occasional Aβ deposits can be found by 6 months with abundant plaques in the hippocampus and cortex by 9 months (Jankowsky et al., 2004) and a progressive increase in plaques up to 12 months (Garcia-Alloza et al., 2006).

Gliosis at 26

Minimal astrocytosis at 3 months; significant astrocytosis by 6 months, especially in areas around plaques. Extensive GFAP+ staining at 15 months and later throughout the cortex (Kamphuis et al., 2012).

Changes in LTP/LTD at 13

Transient long term potentiation (t-LTP) is reduced by 3 months. The degree of impairment is not related to age from 3 to 12 months (Volianskis et al., 2008).

Cognitive Impairment at 52

Impairment in the Morris water maze at 12 months, specifically during acquisition of the hidden platform sub-task and the probe trial but not in the visible platform test (Lalonde et al., 2005). At 13 months the mice commit more errors in the Morris water maze, but not at 7 months (Volianskis et al., 2008).

From the age of 6 months, spatial and non-spatial orientation and memory deficits by Morris water maze. Impaired associative learning. Increased agitation/anxiety from 8 weeks. Reduced ambulation, especially with age. Hyperactivity and aggression.

Observed

Plaques at 13

Robust and reliable plaque pathology as early as 3 months in homozygotes, 5 months in hemizygotes. Plaques start in the anterior neocortex and subiculum, spreading to other brain regions (e.g. hippocampus, thalamus, amygdala). Congophilic dense-core plaques are abundant, with lower levels of diffuse plaques and some cerebral amyloid angiopathy.

Gliosis at 22

Glial activation, including reactive astrocytes and activated microglia, is present in areas around plaques by 5 months of age in homozygous animals, later in hemizygotes.

Synaptic Loss at 13

Decreased expression of synaptophysin mRNA in the brain by 3-4 months of age in both hemizygous and homozygous animals.

Cognitive Impairment at 52

Absent

Tangles at

No tangles or neuropil threads, but some hyperphosphorylated tau by eight months in dystrophic neurites.

Neuronal Loss at

Outright neuronal loss has not been documented, but substantial degeneration of dendritic arbors occurs by 10-14 months of age in hippocampal neurons.

Unknown

Changes in LTP/LTD at

Unknown; however, hippocampal neurons exhibit substantial changes in electrophysiological properties by 10-14 months of age, including hyperexcitability in the form of increased firing of action potentials and a more efficient transition from solitary firing to bursting.

Changes in LTP/LTD at

Age-dependent hyperphosphorylation of tau and conformational changes leading to neurofibrillary tanglelike pathology in the cerebral cortex, hippocampus, brain stem, and spinal cord. Neurodegeneration, especially in the spinal cord, accompanied by astrocytosis.

Early motor impairment, including abnormal clasping and rotarod deficit at 4 months, with nearly complete deficit at 5 months. Deficits progress to severe paraparesis. Disinhibition and hyperactivity at 2 to 3 months.

Observed

Plaques at 22

At 5-7 months of age diffuse amyloid-β plaques deposit in the dentate gyrus and neocortex. Amyloid deposition is progressive with widespread plaques by 8-10 months.

Neuronal Loss at 12

Cell loss varies by brain region. No significant neuronal loss was observed in the CA3 region of the hippocampus at 6, 12, 24 and 36 weeks of age nor in the CA1 region at 6 weeks; however, at 12, 24, and 36 weeks significant neuronal loss was observed in the CA1 region compared to age-matched wild-type animals (Wright et al., 2013).

Gliosis at 24

At 24 and 36 weeks a significant increase in the number of reactive GFAP+ astrocytes and CD68+ microglia was observed in the hippocampi of J20 mice compared to age-matched wild-type controls. No significant difference was observed at 6 and 12 weeks (Wright et al., 2013).

Synaptic Loss at 35

Age-dependent loss of synaptophysin immunoreactivity in presynaptic terminals is observed by 8-10 months, but does not correlate with plaque load (Mucke et al., 2000).

Changes in LTP/LTD at 13

Basal synaptic transmission is impaired between 3-6 months; extracellularly recorded field EPSPs at the Schaffer collateral to CA1 synapse in acute hippocampal slices were on average smaller in amplitude than those seen in wild-type mice. Significant deficits in LTP at the Schaffer collateral–CA1 synapse compared with control mice at 3-6 months (Saganich et al., 2006).

Cognitive Impairment at 16

Deficits in spatial memory and learning appear as the mice age. As early as 16 weeks mice demonstrate spatial reference memory deficits as measured by the radial arm maze (Wright et al., 2013). By 6-7 months deficits appear in spatial memory retention and acquisition in the water maze (Palop et al., 2003).

Learning and memory deficits are age-dependent and may appear as early as 16 weeks. Hyperactivity and increased time in the open arm of the elevated plus maze than wild-type mice indicating lower levels of anxiety, but has not been universally replicated.

Age and gene-dose dependent development of neurofibrillary tangles as early as 4.5 months in homozygotes and 6.5 months in heterozyotes. Tangles and Pick-body-like inclusions in the amygdala, hypothalamus, pons, medulla, and spinal cord among other areas. Neuronal loss, especially in the spinal cord.

By 10 months, 90% developed motor and behavioral disturbances including limb weakness, hunched posture, decrease in grooming and vocalization.

Observed

Plaques at 26

In heterozygous mice no plaque pathology at 4-6 months. At 6-9 months mice begin to exhibit deposits of human Aβ in the hippocampus, corpus callosum, and cerebral cortex. Plaques become more extensive with age and vary in size and structure including diffuse irregular plaques and compact cored plaques (Games et al., 1995).

Synaptic Loss at 35

Changes in LTP/LTD at 17

Alterations in LTP induced by theta burst stimulation at 4-5 months which is prior to plaque formation; although the potentiation immediately after TBS was comparable to control mice, the potentiation decayed more rapidly in PDAPP mice. Also paired pulse facilitation was enhanced. Responses to high frequency stimulation bursts were distorted (Larson et al., 1999).

Observed

Plaques at 26

Large amounts of Aβ accumulate in the cerebral cortex and hippocampus, starting around 6 months and increasing with age. Other brain regions are affected later. Both diffuse and fibrillar plaques form (Gordon et al., 2002).

Neuronal Loss at 79

Neuronal loss in the CA1 region of the hippocampus has been reported at 22 months accompanied by reduced glucose utilization (Sadowski et al., 2004).

Gliosis at 26

GFAP-positive astrocytes appear first in the cortex in the vicinity of the developing Aβ deposits. Numbers increase with age, becoming confluent. Numbers of resting microglia (positive for complement receptor-3) increase in the vicinity of deposits at 6 months, but activated microglia (positive for MHC-II) are negligible before 12 months and more variable (Gordon et al., 2002).

Cognitive Impairment at 12

Double and single transgenic mice had reduced spontaneous alternation performance in a “Y” maze, a test of spatial memory, at 12-14 weeks, before substantial Aβ deposition (Holcomb et al., 1998). Progressive age-related cognitive impairment is seen later in select tasks (e.g. water maze acquisition and radial arm water maze working memory)(Arendash et al., 2001).

Absent

Tangles at

Neurofibrillary tangles are not associated with this model, but hyperphosphorylated tau is detected, starting at 24 weeks, appearing as punctate deposits near amyloid deposits in the cortex and hippocampus (Kurt et al., 2003).

Aβ accumulates in the cerebral cortex and hippocampus starting ~6 months and increasing with age. Other regions affected later. Deposition occurs in white matter, cerebrovasculature, and grey matter in the form of diffuse and fibrillar plaques. Fibrillar deposits are associated with dystrophic neurites and GFAP-positive astrocytes at ~ 6 months with later microglial activation.

Progressive impairment between 5–7 and 15–17 months in some tests of cognitive performance, but not others. No change in anxiety levels.

Observed

Plaques at 52

Fibrillar amyloid plaques develop by 12 months in the cortex and hippocampus.

Gliosis at 26

Astrogliosis and microgliosis underway by 6 months of age in the dentate gyrus.

Synaptic Loss at 104

TAS10 mice initially have more synapses than non-Tg mice; specifically, greater numbers of synapses per neuron were documented at 12 and 18 months of age. However, by 24 months of age, TAS10 mice have fewer synapses than non-Tg mice.

Cognitive Impairment at 26

Deficits in spatial learning present by 6 months of age as measured by the Morris water maze. No difference from non-Tg at 2 months of age. Deficits in Y maze at 12 months. No deficit in fear conditioning up to 24 months of age.

Absent

Tangles at

Absent.

Neuronal Loss at

Qualitative difference in neuronal numbers at 24 months in specific regions of the hippocampus, but no significant neuronal loss.

Changes in LTP/LTD at

At 12 to 14 months of age, deficits in basal synaptic transmission have been observed in the CA1 region, but short- and long-term synaptic plasticity are relatively normal (Brown et al., 2005).

Unknown

Age-related accumulation of Aβ in the hippocampus and cortex leading to plaque deposition by 12 months of age. Early gliosis and dystrophic neurites, not limited to the vicinity around plaques. Changes in synaptic morphology and number, along with increased number of lysosomes.

Deficits in spatial memory prior to Aβ deposition, including deficits in the Morris water maze by 6 months Deficits in spontaneous alternation behavior in the Y maze by 12 months. No deficit in fear conditioning.

Observed

Plaques at 26

Aβ begins to deposit at 3 months of age, with fibrillar plaques evident by 6 months in the cerebral cortex and hippocampus. Some vascular amyloid is also observed. Plaque pathology is more severe in female mice.

Gliosis at 28

Greater numbers of reactive astrocytes and microglia by 6 months of age in the hippocampus and cortex, predominantly near amyloid plaques.

Cognitive Impairment at 26

Age-dependent impairment in object recognition memory starting around 6 months of age for both sexes. No impairment at 3 to 4 months of age.

Absent

Tangles at

Absent.

Neuronal Loss at

Minimal neuronal loss up to 10 months of age. Some signs of loss in the immediate vicinity of plaques in the hippocampus (Howlett et al., 2008).

Aβ deposits beginning at 3 months of age, with fibrillar plaques by 6 months in the cerebral cortex and hippocampus. Some vascular amyloid. Plaques surrounded by dystrophic neurites and reactive glia. No tangles or neuronal loss. Female mice have more rapid and severe amyloid pathology.

Observed

Tangles at 35

Gliosis at 30

Changes in LTP/LTD at 26

Deficit in LTP in CA1 region of the hippocampus at 6 months, but enhanced LTP in the dentate gyrus at a young age (8-10 weeks).

Cognitive Impairment at 22

Age-associated deficit in two cognitive tests that do not depend heavily on motor ability, the passive avoidance task (significant deficit starting at 5 months, but not 2 or 3 months of age) and a novel object recognition task (significant deficit at 9 months, but not at 2, 3, 5, or 7 months of age) (Maurin et al., 2014).

Absent

Plaques at

Absent.

Unknown

Neuronal Loss at

Unknown.

Synaptic Loss at

Unknown at advanced age.
Young mice (1-2 months) have a significantly higher spine maturation index than controls. At 4-6 months, the spine maturation index remains high in the hippocampus, but is reduced to control levels in the cortex. Note, these results were generated using the progeny of Tau P301L x transgenic Thy1-YFP (Kremer et al., 2011).

Pathologic hyperphosphorylation and conformational change of parenchymal tau in brain tissues starting at 7 months. Tangle-like pathology is mainly observed in the brain stem and spinal cord, and to a lesser extent in the midbrain and cerebral cortex. Age-dependent increase in total tau in CSF.

Age-associated deficits in a passive avoidance task (starting at 5 months) and a novel object recognition task (starting at 9 months). At a young age (~2 months) outperforms wild-type littermates in object recognition memory. Progressive motor impairment and reduced activity, accompanied by increased clasping of hind and then forelimbs around seven months.

Absent

Plaques at

Unknown

Neuron loss and brain atrophy by eight to 12 months, especially in the hippocampus and spreading to the neocortex and entorhinal cortex. Neurofibrillary tangles in the neocortex, amygdala, hippocampus, brain stem, and spinal cord. Neuroinflammation with microgliosis and astrocytosis.

Impairments in spatial memory and learning ability in Morris water maze. Paralysis at seven to 10 months associated with a hunched-back posture followed by feeding difficulties. About 80 percent mortality by 12 months with median survival of about nine months.

Observed

Plaques at 48

Numerous parenchymal Aβ plaques by 11-13 months.

Gliosis at 43

Increase in microglial density and size in plaque-forming areas of the brain including the hippocampus, frontal cortex, entorhinal cortex, and occipital cortex in 10-16 month old hemizygotes (Frautschy et al., 1998).

Synaptic Loss at 20

Changes in LTP/LTD at 22

By 5 months, there was a decline in LTP in the dentate gyrus after perforant path stimulation compared to wild-type; impairment was not observed at 2 months (Jacobsen et al., 2006). Both the CA1 and dentate gyrus of aged mice (>15 months) are impaired (Chapman et al., 1999). Differences have been observed between the Schaffer collateral and mossy fiber pathways (Jung et al., 2011).

Cognitive Impairment at 26

Impaired spatial learning, working memory, and contextual fear conditioning at <6 months although other studies have reported normal cognition at this age with progressive impairment by >12 months.

Impaired spatial learning, working memory, and contextual fear conditioning reported at <6 months although other studies have reported normal cognition at this age with progressive impairment by >12 months.

Observed

Plaques at 39

Plaques develop gradually with age. No plaques at 5 months. Very few small plaques at 6 and 7 months. By 9 months plaques scattered throughout the cortex, hippocampus and amygdala, continue to increase at 12 months. Similar distribution as Tg2576.

Tangles at 13

Neurofibrillary tangles in the spinal cord and pons as early as 3 months, but more consistent and numerous by 6 months. Tangles morphologically similar to those in JNPL3 mice but older bigenic female mice had a marked increase in neurofibrillary tangles in limbic areas by 6 months, especially the olfactory cortex, entorhinal cortex and amygdala (Lewis et al., 2001).

Gliosis at 13

Reactive astrocytes and microglia as early as 3 months in the hippocampus as measured by GFAP and CD45. Increased astrocytosis with age especially in limbic areas with the most neurofibrillary tangles. Microglia especially concentrated around plaques at 9 and 12 months (Lewis et al., 2001).

Absent

Unknown

Synaptic Loss at

Gradual appearance of plaques; by 9 months plaques are scattered throughout the cortex, hippocampus, and amygdala similar to Tg2576. Tau pathology more extensive than JNPL3. Astrocytosis and microgliosis.

Motor disturbances similar to JNPL3, with identical range in age of onset. Reduced vocalization and decreased grooming.

Early impairment in acquisition and learning reversal in the reference memory version of the Morris water maze by 3 months. Cognitive deficits in the step-down inhibitory avoidance test at 7 months but not at 2 months. Similar to wild-type in motility, exploratory activity, or neuromuscular function at 7 months as evaluated by the rotarod, hole board and grip strength tests.